The pathology of traumatic brain injury in experimental models includes acute inflammatory reaction, blood brain barrier disruption, hemorrhage, demyelination, axonal transection and chronically with axonal neuronal loss and gliosis. Stem cell (SC) therapy is a potential treatment either as replacement therapy or via paracrine effect with release of growth factors and anti-inflammatory cytokines for TBI injury. Experimental studies in rodent models of TBI have been limited and usually a single dose of cells is administered within 24 to 72 hours after experimental injury. The optimal timing and dose of cell delivery to maximize functional recovery and transplantation survival during the acute inflammatory and edematous phase of damage is unknown. We evaluated the natural history of control cortical impact (CCI) to induce TBI in the rat brain by serial MRI, molecular biological and histological analysis. Following TBI, inflammatory macrophages (M1) predominate over anti-inflammatory macrophages (M2). We investigated the temporal profile of M1/M2 phenotypes in macrophages and microglia after CCI and examined the post-injury M1/M2 time course in brain. Separate cohorts of rats had their brains either dissociated into cells for flow cytometry, perfusion-fixed for immunohistochemistry (IHC) and ex vivo magnetic resonance imaging (MRI), or flash frozen for RNA/protein analysis at 24 hours, 3 or 5 days, or 1, 2, 4, or 8 weeks following CCI. The macrophage/microglial response peaked at 5 to 7 days post-TBI, with characteristics of mixed populations of M1 and M2 phenotypes. By flow cytometry of immunological cells isolated from brain tissue, a peak of M2-associated staining occurred at 5 days post-TBI. Chemokine analysis by multiplex assay showed statistically significant increases in macrophage inflammatory protein-1a and Mouse keratinocyte-derived cytokine on the ipsilateral side within the first 24 hours after injury relative to control and to the contralateral side. Quantitative real time polymerase chain reaction (qRT-PCR) analysis demonstrated expression of both M1- and M2-associated markers peaking at 5 days post-TBI. The macrophage/microglial response to histologically severe CCI in the female rat is maximal between days 3 and 7. The brain microenvironment has elements of both pro- and anti-inflammatory responses within the first week after traumatic injury, rather than one that is clearly skewed more towards an M1 versus M2 phenotype. A spectrum of macrophage and microglial phenotypes exists after CCI, likely reflecting a complex inflammatory response in which the cells may adjust their functions based upon the post-traumatic milieu. This mixed pattern has relevance to translation of results to clinical populations as to when to possibly institute treatment to down-regulate inflammation or stimulate repair process.